JP2021529318A - Magnesium ion selective membrane - Google Patents

Abstract

Magnesium ion-selective electrode membrane and its preparation. The membrane contains a lipophilic compound containing an acidic group (eg, bis-4-octylphenylphosphate) covalently attached to a C4-C18 alkyl-substituted phenyl group and magnesium-selective ionophores (eg, neutral ionophores 1,10). The acidic group is preferably a PVC film, either by introducing it into a membrane containing a −phenanthroline derivative) or by covalently bonding an acidic (eg, carboxylic acid) group to an ionophore (eg, a 1,10-phenanthroline derivative). By adding to, high selectivity for magnesium ions is imparted. [Selection diagram] Fig. 1

Description

The present invention relates to magnesium ion selective membranes and their preparation, electrodes and potential difference measurement sensors containing such membranes, and their use for determining magnesium ion concentration in a sample.

Magnesium is a common metal in the human body and plays an important role in chemical and biochemical processes. Magnesium in the body either binds to proteins and forms complexes with anions, or exists as a free ionization fraction (iMg). The iMg fraction plays several physiological roles, for example, as an ion channel regulator in nerve conduction or contraction of skeletal muscle, myocardium or uterine muscle. A study in inpatients found a high prevalence of hypomagnesemia (11%) and hypermagnesemia (9.3%) (Wong et al. (1983) Am J Clin Pathol 79: 348). ).

Specific measurements of iMg have been difficult, and historically, laboratory tests have often relied on an assay for magnesium as a whole. Magnesium ion-selective sensors are described in WO 92/16831 (Nova Biomedical Corp.), which discloses a magnesium-selective membrane containing 1,10-phenanthroline as a magnesium ion-selective compound. WO2015 / 160755 (Siemens Healthcare Diagnostics Inc.) describes a membrane for detecting ionized magnesium, including ionophores, lipophilic borates and polymer matrices with a tripod stereochemical structure.

However, imparting high selectivity for iMg to the membrane, especially obtaining selectivity for magnesium ions as compared to other cations such as calcium ions, remains a challenge. In addition to limited selectivity, magnesium ion selective membranes described in the art are often suboptimal in terms of stability, interference, drift and rapid rise time. Adjustments to improve the membrane for one of these parameters may adversely affect the other parameters.

Therefore, there is a need for an improved magnesium ion sensor that is highly selective for magnesium but still stable, resistant to interference and drift, and has a rapid rise time. These needs are addressed by the present invention.

In the first aspect, the present invention is a. Ionophore, and b. A lipophilic compound containing an acidic group, of formula I

(During the ceremony,
A contains an acidic group
One, two or all three of R ¹⁸ , R ¹⁹ and R ²⁰ _{are C 4-18} alkyl groups, C _4-18 alkenyl groups, C _4-18 alkynyl groups or amide-containing C _4-18 groups. a _{C 4 to 18} group is the _{C 4 to 18} groups, or 1, 2 and 3, calculated from the phenyl group is a straight chain or a side chain in total the 1, 2 and 3 of Have only one
The other R ¹⁸ , R ¹⁹ and R ²⁰ are independently hydrogen or linear C _1-18 alkyl groups).
Provided is a magnesium ion-selective membrane containing a lipophilic compound, which is a compound of the above, or a salt of the lipophilic compound.

In a further aspect, the present invention
i) an ionophore covalently bonded to an acidic group via a spacer, the spacer containing at least one carbon atom, an ionophore, or ii) its salt, i.e., covalently bonded to an acidic group via a spacer. Provided is a magnesium ion-selective membrane containing the salt of the ionophore.

In a further embodiment, the invention is a method of preparing a magnesium ion selective membrane of the invention, in which the components are mixed in a solvent, the resulting solution is distributed onto a desired support and the solvent is evaporated. By the way.

In a further aspect, the invention provides an electrode for determining the magnesium ion concentration of a liquid sample, comprising the membrane of the invention as defined herein.
In a further aspect, the present invention provides a potential difference measuring sensor for determining the magnesium ion concentration of a liquid sample, which comprises the membrane of the present invention or the electrode of the present invention.

Further, the present invention is a method for determining the magnesium ion concentration of a liquid sample, which is obtained from a step of contacting the sample with the electrode of the present invention or the potentiometric titration sensor of the present invention and the electrode or the potentiometric titration sensor. The present invention relates to a method including a step of determining a magnesium ion concentration based on a signal. The present invention also relates to a method of diagnosing a disease or disorder, comprising the step of performing a method of determining magnesium ion concentration for a sample of interest in accordance with the present invention.

These and other aspects and embodiments of the present invention are described in more detail below.

および感度（Ｓ）を決定するために使用したＦＩＭ溶液について記録された真のｃＭｇ値の関数としての信号ｍＶを示すグラフである。灰色の陰影部分は、イオン化マグネシウムの生理学的に適切な測定範囲（０．１〜２．５ｍＭ）を示す。ｘ軸は対数である。
膜ＩＤ：「ＤＵＰ＿ＯＰＰ」、「ＤＵＰ＿テトラキス」、「ＭＵＰ＿ＯＰＰ」、「ＥＴＨ５５０６＿ＯＰＰ」および「ＥＴＨ５５０６＿テトラキス」で調製したイオン選択性電極の選択係数

および感度（Ｓ）を決定するために使用したＦＩＭ溶液について記録された真のｃＭｇ値の関数としての信号ｍＶを示すグラフである。灰色の陰影部分は、イオン化マグネシウムの生理学的に適切な測定範囲（０．１〜２．５ｍＭ）を示す。ｘ軸は対数である。 Membrane ID: Selection coefficient of ion-selective electrode prepared with "OPP", "OBA", "OBS", "DBS" and "Tetrakis"

And a graph showing the signal mV as a function of the true cMg value recorded for the FIM solution used to determine the sensitivity (S). The gray shaded area indicates a physiologically appropriate measurement range (0.1 to 2.5 mM) of ionized magnesium. The x-axis is logarithmic.
Membrane ID: Selection coefficient of ion-selective electrode prepared with "DUP_OPP", "DUP_Tetrakis", "MUP_OPP", "ETH5506_OPP" and "ETH5506_Tetrakis"

And a graph showing the signal mV as a function of the true cMg value recorded for the FIM solution used to determine the sensitivity (S). The gray shaded area indicates a physiologically appropriate measurement range (0.1 to 2.5 mM) of ionized magnesium. The x-axis is logarithmic.

Definition As used herein in the context of membranes, the term "selectivity" refers to a preference for a particular ion. As used herein, "selectivity" does not mean absolute or exclusive selectivity. That is, the membrane may be selective for multiple ions, such as magnesium and calcium ions.

As used herein, the term "ionophore" refers to a compound that reversibly binds ions, such as a compound that can transport ions throughout the membrane.
In particular, in the context of "lipophilic compounds", the term "lipophilic" as used herein refers to the ability of chemical compounds to dissolve in fats, oils, lipids or non-polar solvents.

The term "acidic group" refers to a group that can donate hydrogen ions to a base for ionization.
As used herein, the term "salt" refers to an acid deprotonated form with a cation species that equilibrates its negative charge.

As used herein, the term "substitution form" of 1,10-phenanthroline refers to a substance comprising a 1,10-phenanthroline backbone that comprises one or more substitutions thereof. The term "substitution" refers to the substitution of hydrogen on 1,10-phenanthroline at an R group or R residue. Similarly, "substituted aryl" refers to an aryl group in which hydrogen is replaced by a different residue or group.

In the context of a chemical group, _{the term "C xx to yy} " indicates that the group contains XX to YY carbon atoms, i.e. any number starting from XX and up to YY, including YY. For example, a C _1-18 alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms. contains. Unless otherwise stated, such groups can be linear or branched.

When referring to a chemical group, the terms "alkyl," "aryl," "alkenyl," and "alkynyl" have their usual meaning in the art. In some embodiments, such groups contain up to 18 carbon atoms. The term "branched alkyl" refers to an alkyl group that is not completely linear, i.e., has at least one side chain.

As used herein in the context of determining the concentration of ions, such as magnesium ions in a sample, the term "concentration" refers to the ions in a standardized solution matrix that have ionic activity equal to that of the measured sample. Refers to stoichiometric concentration (reference scale). See IFCC Guidelines (Ben Rayana et al. (2008) Clin Chem Lab Med 46 (1): 21).

The term molecular weight as used herein in relation to polymers is
M _w = ΣW _i M _i
(Wherein, W _i is the weight fraction of the polymer having a molecular weight M _i)
Refers to the weight average molecular weight calculated by.

Further Aspects and Embodiments of the Invention The inventors have developed a magnesium ion-selective membrane with improved selectivity for magnesium ions as compared to the membranes previously described in the art. In addition, the films of the invention are stable, resistant to interference and drift, and have a rapid rise time.

Improvements in selectivity are achieved by adding acidic groups to the membrane by either introducing a lipophilic compound containing the acidic group into the membrane or covalently attaching the acidic group to the ionophore used in the membrane. NS.

Without being bound by any theory, it is hypothesized that structures that favor the interaction of ionophores with, for example, magnesium ions over larger calcium ions, such as those shown below, can be formed.
Structure A:

Structure B:

Therefore, as described above, in the first aspect, the present invention is:
a. Ionophore, and b. A lipophilic compound containing an acidic group, of formula I

(During the ceremony,
A contains an acidic group
One, two or all three of R ¹⁸ , R ¹⁹ and R ²⁰ _{are C 4-18} alkyl groups, C _4-18 alkenyl groups, C _4-18 alkynyl groups or amide-containing C _4-18 groups. a _{C 4 to 18} group is the _{C 4 to 18} groups, or 1, 2 and 3, calculated from the phenyl group is a straight chain or a side chain in total the 1, 2 and 3 of Have only one
The other R ¹⁸ , R ¹⁹ and R ²⁰ are independently hydrogen or linear C _1-18 alkyl groups).
The present invention relates to a magnesium ion-selective membrane containing a lipophilic compound, which is a compound of the above, or a salt of the lipophilic compound.

For the avoidance of doubt, the expression "or having only one side chain in total at the 1, 2 and 3 positions" in this specification means that each C _4-18 group is in the 1, 2 and 3 positions. It means having only one side chain in total. Thus, in embodiments where two or more of ^{R 18} , R ¹⁹ and R ²⁰ _{are C 4-18} , two or more of these C _4-18 are in the 1, 2 or 3 position. It may have one side chain.

For illustration purposes, the following formula illustrates one embodiment in which R ¹⁸ and R ²⁰ are hydrogen and R ¹⁹ is a linear C ₈ alkyl group containing no side chains. 1st, 2nd and 3rd place

Indicated by.
Further, as described above, in a further aspect, the present invention is:
i) The ionophore covalently bonded to an acidic group via a spacer, said ionophore containing at least one carbon atom, or ii) its salt, i.e. shared to an acidic group via a spacer. Provided is a magnesium ion-selective membrane containing the bound salt of the ionophore.

Ionophore The magnesium ion-selective membrane of the present invention contains an ionophore or a mixture of ionophores. The ionophore used in the membrane of the present invention may or may not be charged (neutral). In some embodiments, the ionophore is lipophilic.

In a preferred embodiment, the ionophore is 1,10-phenanthroline or a phenanthroline compound which is a substitution form thereof. Such compounds are described, for example, in WO 92/16831 (Nova Biomedical Corp.). 1,10-Phenanthroline has the following structure

Have.
In one embodiment, the carbon atoms at positions 2 and 9 of the phenanthroline compound are bonded to hydrogen.

In one embodiment, the ionophore is formulated in Equation II.

[During the ceremony,
R ^{1 to} R ⁶ are each
H,
Either F, Cl, Br, I, NO ₂ , CN or CF _3,
C _1-18 alkyl,
C _1-18 aryl,
C _1-18 alkenyl,
(CH ₂ ) _m Y (in the formula, m is an integer of 0 or 1-4, where Y is -OR ⁷ , -NR ⁷ R ⁸ , -OCOR ⁷ , -NR ⁷ COR ⁸ , -COR ⁷ , -COOR. ⁷ , -SO ₃ R ⁷ , -OSiR ⁷ R ⁸ R ⁹ , -PO ₄ R ⁷ R ⁸ , -PO ₃ R ⁷ R ⁸ , where R ⁷ , R ⁸ and R ⁹ are H, respectively. Alkyl, branched alkyl, aryl or substituted aryl), or C _n −R ¹⁰ R ¹¹ (in the formula, n is an integer of 1 to 17 including 0, or 1 and 17, where R ¹⁰ is C. , N, NCO or CH _2- Z-CH ₂ , where Z is either O, NH, S, OCO or CO, and R ¹¹ is Formula III.

R ¹¹ is attached to ^{R 10} at any of the 3, 4, 5, 6, 7 or 8 positions of ^{R 11 , and R 12 to} R ¹⁷ are H, C _{1 to 18} alkyl, C. _{If it is either 1 to 18} aryl or is removed, except that R ¹¹ is ^{attached to R 10} at the 3-position of R ¹¹ , then R ¹² is removed and R ¹¹ is at the 4-position of ^{R 11.} When bound to ^{R 10 , R 13} is removed, and when R ¹¹ is bound to ^{R 10} at the 5th position of R ^{11 , R 14} is removed and R ¹¹ is at the 6th position of R ^{11 and R 10} If R ¹⁵ is removed and R ¹¹ is ^{attached to R 10} at the 7th position of R ¹¹ , then R ¹⁶ is removed and R ¹¹ is attached ^{to R 10} at the 8 position of R ^11. If so, R ¹⁷ will be removed)
Is either, provided ^that one of R 1 to R ^6, are other than H, and 2 and 9 C atoms of the 1,10-phenanthroline are each a bond which is not involved in fused ring structure, Combined with H]
It is a compound of.

In a further embodiment, R ^{1 to} R ⁶ are a total of at least 6 carbon atoms, such as 6, 7, 8, 9, 10 or 11 carbon atoms, such as a total of at least 11 carbon atoms. For example, it contains 11 to 18 carbon atoms.

In another embodiment, ^{one or more of R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is an alkyl or aryl group having 1 to 18 carbon atoms. For example, ^{one or two groups selected from R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ can be alkyl or aryl groups with 1-18 carbon atoms, the others. Hydrogen, for example, R ¹ and R ² , R ¹ and R ³ , R ¹ and R ⁴ , R ¹ and R ⁵ , R ¹ and R ⁶ , R ² and R ³ , R ² and R ⁴ , R ² And R ⁵ , R ² and R ⁶ , R ³ and R ⁴ , R ³ and R ⁵ , R ³ and R ⁶ , R ⁴ and R ⁵ , R ⁴ and R ⁶ or R ⁵ and R ⁶ are 1 to 18 It is an alkyl or aryl group with a number of carbon atoms, the other group being hydrogen.

In another embodiment, ^{one or more of R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is an alkyl group having 1 to 18 carbon atoms. For example, ^{one or two groups selected from R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ can be alkyl groups with 1-18 carbon atoms, the other with hydrogen. Yes, for example, R ¹ and R ² , R ¹ and R ³ , R ¹ and R ⁴ , R ¹ and R ⁵ , R ¹ and R ⁶ , R ² and R ³ , R ² and R ⁴ , R ² and R. ⁵ , R ² and R ⁶ , R ³ and R ⁴ , R ³ and R ⁵ , R ³ and R ⁶ , R ⁴ and R ⁵ , R ⁴ and R ⁶ or R ⁵ and R ⁶ are 1 to 18 pieces. It is an alkyl having a carbon atom, and the other R group is hydrogen.

In another embodiment, ^{one or more of R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is an alkyl group having 6-18 carbon atoms. For example, ^{one or two groups selected from R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ can be alkyl groups with 6-18 carbon atoms, the other with hydrogen. Yes, for example, R ¹ and R ² , R ¹ and R ³ , R ¹ and R ⁴ , R ¹ and R ⁵ , R ¹ and R ⁶ , R ² and R ³ , R ² and R ⁴ , R ² and R. ⁵ , R ² and R ⁶ , R ³ and R ⁴ , R ³ and R ⁵ , R ³ and R ⁶ , R ⁴ and R ⁵ , R ⁴ and R ⁶ or R ⁵ and R ⁶ are 6 to 18 pieces. It is an alkyl group having a carbon atom, and the others are hydrogen.

In another ^embodiment, only one of ^{R 1, R 2, R 3} , R 4, R 5 and ^{R 6,} 1 to 18 carbon atoms, for example, 6 to 18 carbon atoms, e.g. It is an alkyl group having 11 to 18 carbon atoms, and the other R group is hydrogen.

In another embodiment, R ² and / or R ⁵ is an alkyl group having 1-18 carbon atoms, eg 6-18 carbon atoms, eg 11-18 carbon atoms, and other The R group is hydrogen. In another embodiment, R ² and / or R ⁵ is an aryl group having 1 to 18 carbon atoms.

In a preferred embodiment, the ionophore is 4-undecylic-1, 10-phenanthroline or 4,7-diundesyl-1,10-phenanthroline.
Substituted 1,10-phenanthroline compounds can be synthesized by standard techniques known to those of skill in the art. For example, the synthesis of 4- and 4,7-substituted 1,10-phenanthrolines is incorporated herein by reference, Lund et al., J. Mol. Chem. Eng. Data, 26: 227-29 (1981). Methyl groups can provide a handle for attachment of the desired side chain in the synthesis of other 1,10-phenanthroline derivatives, and methyl substituted 1,10-phenanthroline is commercially available. For example, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 3,6-dimethyl, 5,7-dimethyl, 4,7-dimethyl and 5,6-dimethyl-1,10-phenanthroline are all Aldrich. Chemical Co. Available from. 4-Undecylic-1, 10-phenanthroline and 4,7-diundesyl-1,10-phenanthroline can be synthesized, for example, as described in WO 92/16831 (Nova Biomedical Corp.).

In another embodiment, the magnesium ion-selective membrane comprises an ionophore having a tripod stereochemical structure, eg, a tripod structure, eg, one described in WO2015 / 160755 (Siemens Healthcare Diagnostics Inc.).

Therefore, in one embodiment, the ionophore is of formula IV.

(Also referred to as ETH5506 in the art).
In another embodiment, the ionophore is of formula V.

(Also referred to as ETH5504 in the art).
In another embodiment, the ionophore is the formula VI.

(Also referred to as ETH3832 in the art).
In another embodiment, the ionophore is of formula VII.

(In the formula, n is an integer of 6 to 8)
(If n is 6, it is referred to as ETH5282 in the art, and if n is 8, it is referred to as ETH7025 in the art).

In another embodiment, the ionophore is one of the ionophores listed in Table 8 of IUPAC 2000 Part I Organic chemistry Pure Appl Chem 72: 1851, eg, Mg ^{2 +} -1, Mg ²⁺ -2, Mg 2 ⁺ -. 3, Mg ²⁺ -4, Mg ²⁺ -5, Mg ²⁺ -6, Mg ²⁺ -7, Mg ²⁺ -8, Mg ²⁺ -9, Mg ²⁺ -10, Mg ²⁺ -11, Mg ²⁺ -12, Mg 2 ⁺ - 13, Mg ²⁺ -14, Mg ²⁺ -15, Mg ²⁺ -16, Mg ²⁺ -17, Mg ²⁺ -18, Mg ²⁺ -19, Mg ²⁺ -20, Mg ²⁺ -21, Mg ²⁺ -22, Mg 2 ⁺ - 23, Mg ²⁺ -24, Mg ²⁺ -25, Mg ²⁺ -26, Mg ²⁺ -27, Mg ²⁺ -28, Mg ²⁺ -29, Mg ²⁺ -30, Mg ²⁺ -31, Mg ²⁺ -32, Mg 2 ⁺ - 33, Mg ²⁺ −34, Mg ²⁺ −35, Mg ²⁺ −36, Mg ²⁺ −37, Mg ²⁺ −38, Mg ²⁺ −39, Mg ²⁺ −40, Mg ²⁺ −41, Mg ²⁺ −42, Mg ²⁺ − 43, Mg ²⁺ -44, Mg ²⁺ -45, Mg ²⁺ -46, Mg ²⁺ -47, Mg ²⁺ -48, Mg ²⁺ -49, Mg ²⁺ -50, Mg ²⁺ -51, Mg ²⁺ -52, Mg 2 ⁺ - 53, Mg ²⁺ −54, Mg ²⁺ −55 or Mg ²⁺ −56.

In another embodiment, the ionophore is described in Buhlmann et al. (1998) Chem. Rev. One of the ionophores described in 98: 1593, for example, Mg ²⁺ -1, Mg ^{2 +} -2, Mg ²⁺ -3, Mg 2 ⁺ -4, Mg ²⁺ -5, Mg ²⁺ -6, Mg ²⁺ -7. , Mg ²⁺ -8, Mg ²⁺ -9, Mg ²⁺ -10, Mg ²⁺ -11, Mg ²⁺ -12, Mg ²⁺ -13, Mg ²⁺ -14, Mg ²⁺ -15 or Mg ²⁺ -16.

In another embodiment, the ionophore is ETH5220 (Zhang et al. (2011) Am. J. Biomed. Sci. 3: 301) or ETH 2001, ETH 2002, ETH 2003 or ETH 2022 (Zhang et al. (2000) Anal. Sci. 16:11). Is.

In another embodiment, the ionophores are all ETH1001, DBM, ETH1117, cyclo (LPro-DLeu) ₅ , ETH1224, ETH2220, ETH4030, ETH5214, ETH5282 or ETH228, as described in Spichiger (1993) Electronalesis 5: 739.

In another embodiment, the ionophore is described by Suzuki et al. (1995) Anal. Chem. One of the ionophores described in 67: 324 (incorporated herein by reference), preferably K22B5, an 18-membered diaza crown with two malonamide side chains having an adamantyl group, or a variant thereof. , For example, K22B1B5 (Siswanta et al. (1997) Anal. Sci. 13: 429).

In a preferred embodiment, the ionophore is 1,2-bis (diarylphosphine oxide) benzene (Saleh (1994) J. Electroanalytical Chem. 373: 89) or methylphenyl semicarbazone (Chandra et al. (2013) J. Chem., http: //dx.doi.org/10.1155/2013/189464).

Lipophilic compounds As described above, in the first aspect, the present invention
a. Ionophore, and b. A lipophilic compound containing an acidic group, of formula I

(During the ceremony,
A contains an acidic group
One, two or all three of R ¹⁸ , R ¹⁹ and R ²⁰ _{are C 4-18} alkyl groups, C _4-18 alkenyl groups, C _4-18 alkynyl groups or amide-containing C _4-18 groups. a _{C 4 to 18} group is the _{C 4 to 18} groups, or 1, 2 and 3, calculated from the phenyl group is a straight chain or a side chain in total the 1, 2 and 3 of Have only one
The other R ¹⁸ , R ¹⁹ and R ²⁰ are independently hydrogen or linear C _1-18 alkyl groups).
Provided is a magnesium ion-selective membrane containing a lipophilic compound, which is a compound of the above, or a salt of the lipophilic compound.

Therefore, the membrane of this aspect of the present invention comprises a lipophilic compound of formula I or a salt thereof.
In one embodiment, the acidic group contained in Group A of Formula I is a carboxylic acid, sulfonic acid, sulfuric acid monoester, sulfonamide, phosphonic acid, phosphoric acid, arsenic, sulfinic acid or thiocarboxylic acid.

In one embodiment, the acidic group contained in the A group of formula I is a carboxylic acid. For example, the A group can be a carboxylic acid group of formula IX, a carbonate group of formula X, an oxalic acid monoester group of formula XI or a dicarboxylic acid monoester group of formula XII:
Formula IX

Formula X

Formula XI

Formula XII

R ²³ can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group, or R ²³ is absent. Can be. Preferably, R ²³ is linear. For example, in one embodiment of the compound of formula IX, R ²³ is absent and therefore the A group consists of a carboxylic acid group. ^{R 24} of the formula IX can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group.

In another embodiment, the acidic group contained in the A group is a sulfonic acid. For example, the A group can be a sulfonic acid group of formula XIII:
Equation XIII

R ²³ can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group, or R ²³ is Can be absent. Preferably, R ²³ is linear. For example, in one embodiment of the compound of formula XIII, R ²³ is absent and therefore the A group consists of a sulfonic acid group.

In another embodiment, the acidic group contained in Group A is sulfuric acid monoester. For example, the A group can be a sulfuric acid monoester group of formula XIV:
Formula XIV

R ²³ can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group, or R ²³ is Can be absent. Preferably, R ²³ is linear. For example, in one embodiment of the compound of formula XIV, R ²³ is absent and therefore the A group consists of a sulfuric acid monoester group.

In another embodiment, the acidic group contained in the A group is a sulfonamide. For example, the A group can be a sulfonamide group of formula XV:
Formula XV

R ²³ can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group, or R ²³ is Can be absent. Preferably, R ²³ is linear. For example, in one embodiment of the compound of formula XV, R ²³ is absent and therefore the A group consists of a sulfonamide group.

In another embodiment, the acidic group contained in the A group is a phosphonic acid. For example, the A group can be a phosphonic acid group of formula XVI or a phosphonic acid monoester group of formula XVII:
Formula XVI

Formula XVII

R ²³ can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group, or R ²³ is Can be absent. Preferably, R ²³ is linear. For example, in one embodiment of the compound of formula XVI, R ²³ is absent and therefore the A group consists of a phosphonic acid group. R ²⁴ can be a C _1-18 group, eg, a C _1-18 alkyl group, a C _1-18 alkenyl group, a C _1-18 alkynyl group, an amide-containing C _1-18 group or an aryl group. In particular, the aryl group can be a phenyl group, for example R ²⁴ can be a phenyl group having ^{substituents R 18} , R ¹⁹ and R ²⁰ as defined in Formula I.

In another embodiment, the acidic group contained in the A group is phosphoric acid. For example, the A group can be a phosphate monoester group of formula XVIII, or a phosphoric acid diester group of formula XIX, or a polyphosphoric acid group of formula XX:
Formula XVIII

Formula XIX

Formula XX

R ²³ can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group, or R ²³ is Can be absent. Preferably, R ²³ is linear. For example, in one embodiment of the compound of formula XVIII, R ²³ is absent and therefore the A group consists of a phosphate monoester group. In one embodiment of the compound of formula XIX, R ²³ is absent and therefore the A group consists of a phosphodiester group. R ²⁴ can be a C _1-18 group, eg, a C _1-18 alkyl group, a C _1-18 alkenyl group, a C _1-18 alkynyl group, an amide-containing C _1-18 group or an aryl group. In particular, the aryl group can be a phenyl group, for example R ²⁴ can be a phenyl group having ^{substituents R 18} , R ¹⁹ and R ²⁰ as defined in Formula I.

In another embodiment, the acidic group contained in the A group is arsenic acid. For example, the A group can be a group of formula XVI, XVII, XIII, XIX or XX, where the phosphorus atom is replaced with an arsenic atom (As).

In another embodiment, the acidic group contained in the A group is sulfinic acid. For example, the A group can be a sulfinic acid group of formula XXI:
Formula XXI

R ²³ can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group, or R ²³ is absent. Can be. Preferably, R ²³ is linear. For example, in one embodiment of the compound of formula XXI, R ²³ is absent and therefore the A group consists of a sulfinic acid group.

In another embodiment, the acidic group contained in the A group is a thiocarboxylic acid. For example, group A can be a thiocarboxylic acid group of formula XXII or formula XXIII:
Formula XXII

Formula XXIII

R ²³ can be a C _1-5 group, eg, a C _1-5 alkyl group, a C _1-5 alkenyl group, a C _1-5 alkynyl group or an amide-containing C _1-5 group, or R ²³ is absent. Can be. Preferably, R ²³ is linear. For example, in one embodiment of a compound of formula XXII or formula XXIII, R ²³ is absent and therefore the A group consists of a thiocarboxylic acid group.

In one embodiment, A group of the formula I are phosphoric acid monoesters or diesters groups, such as Formula XIX of _{^{-R 23 - (HPO 4) -R}} 24 group ^(wherein, either ^{R 23} is absent, or alkyl _{(e.g., C 1 to 18} alkyl), branched alkyl, aryl or substituted ^{aryl, R 24} is hydrogen or alkyl _{(e.g., C 1 to 18} alkyl), branched alkyl, aryl or substituted aryl).

In a further embodiment, the lipophilic compound is of formula VIII.

(In the formula, R ¹⁸ , R ¹⁹ and R ²⁰ are as defined for formula I)
Contains the compounds of. Preferably, the membrane comprises a salt of a lipophilic compound of formula VIII.
In one embodiment, one of R ¹⁸ , R ¹⁹ or R ²⁰ is a C _4-18 alkyl group as defined above (ie, the 1, 2 and 3 positions counting from the phenyl group are linear. _{Or a C 4-18} alkyl group having only one side chain in total at the 1, 2 and 3 positions above), and the others are independently hydrogen or linear C _1-18 alkyl groups.

In a further embodiment, one of R ¹⁸ , R ¹⁹ or R ²⁰ is a C _4-18 alkyl group as defined above and the other is hydrogen. In a further embodiment, R ¹⁹ _{is a C 4-18} alkyl group as defined above and ^{R 18} and R ²⁰ are hydrogen.

In one embodiment, the _C4-18 alkyl groups (s) are linear. In another embodiment, the _C4-18 alkyl group (s) comprises at least 6 carbon atoms, eg, at least 8 carbon atoms, eg, 8, 9, 10, 11 or 12 carbon atoms.

In a further embodiment, only one of ^{R 18} , R ¹⁹ or R ²⁰ _{is a C 4-18} alkyl group, said C _4-18 alkyl group having at least 6 carbons, eg at least 8 carbons. Includes atoms such as 8, 9, 10, 11 or 12 carbon atoms.

In a preferred embodiment, the lipophilic compound comprises a compound of formula VIII, where R ¹⁸ and R ²⁰ are hydrogen and R ¹⁹ is an octyl group.
In a preferred embodiment, the lipophilic compound is provided in the form of a salt. Preferred salts are magnesium and calcium salts.

In a preferred embodiment, the lipophilic compound is hemicalcium bis [4-octylphenyl] phosphate, hemimagnesium bis [4-octylphenyl] phosphate or a mixture of two salts thereof.

Lipophilic compounds, such as hemicalcium bis [4-octylphenyl] phosphate and hemimagnesium bis [4-octylphenyl] phosphate, can be prepared by standard methods known in the art.

In a preferred embodiment, the lipophilic salt is a mixture of hemicalcium bis [4-octylphenyl] phosphate and hemimagnesium bis [4-octylphenyl] phosphate, the mixture being at least 50% hemimagnesium bis [4-octylphenyl] phosphate. It contains at least 80% hemimagnesium bis [4-octylphenyl] phosphate, such as 80% to 90% hemimagnesium bis [4-octylphenyl] phosphate.

In a more preferred embodiment of the magnesium ion selective membrane of the present invention, the ionophore is 4,7-diundecyl-1,10-phenanthroline and the lipophilic salts are hemimagnesium bis [4-octylphenyl] phosphate and hemicalcium. It is a mixture with bis [4-octylphenyl] phosphate.

In a preferred embodiment, the molar ratio of ionophore to lipophilic compound or lipophilic salt (s) anion (s) is 2: 1 to 1: 1, for example 1.8: 1 to 1.2: 1. The molar ratio of.

In addition to the lipophilic compounds and lipophilic salts described above, additional salts may be present in the membrane of the present invention. Thus, in embodiments, the membranes of the invention contain additional salts such as tetrakis (4-chlorophenyl) borate.

Ionophores Containing Covalently Bonded Acid Groups In a further aspect of the invention, the ionophores and acidic groups are covalently bonded rather than part of a separate compound.

Therefore, in a major aspect, the present invention is:
An ionophore covalently bonded to an acidic group via a spacer, wherein the spacer contains at least one carbon atom, or an ionophore covalently bonded to an acidic group via a spacer. For magnesium ion-selective membranes containing salts.

In a preferred embodiment, the ionophore is lipophilic.
In one embodiment, the spacer is an alkyl group, eg, a linear or branched alkyl group having a total of 1-18 carbon atoms, with the alkyl group optionally substituted. In another embodiment, the spacer is a linear alkyl group, eg, a − (CH ₂ ) _n − group (where n is at least 1, eg, 1, 2, 3, 4 or 5, or at least 2). There is).

In one embodiment, the ionophore is 1,10-phenanthroline or a phenanthroline compound which is a substitution form thereof. In one embodiment of the specification, the spacer is covalently attached to the phenanthroline compound at the carbon atom at position 2, 3, 4, 5, 6, 7, 8 or 9 of 1,10-phenanthroline.

In a further embodiment, the ionophore covalently attached to an acidic group via a spacer, said spacer containing at least one carbon atom, is of formula II.

[During the ceremony,
R ^{1 to} R ⁶ are each
H,
Either F, Cl, Br, I, NO ₂ , CN or CF _3,
C _1-18 alkyl,
C _1-18 aryl,
C _1-18 alkenyl,
(CH ₂ ) _m Y (in the equation, m is an integer of 0 or 1-4, where Y is -OR ⁷ , -NR ⁷ R ⁸ , -OCOR ⁷ , -NR ⁷ COR ⁸ , -COR ⁷ , -COOR. ⁷ , -SO ₃ R ⁷ , -OSiR ⁷ R ⁸ R ⁹ , -PO ₄ R ⁷ R ⁸ , -PO ₃ R ⁷ R ⁸ , where R ⁷ , R ⁸ and R ⁹ are H, respectively. Alkyl, branched alkyl, aryl or substituted aryl),
C _{n −} R ¹⁰ R ¹¹ (in the equation, n is an integer of 1 to 17 including 0, or 1 and 17, R ¹⁰ is C, N, NCO or CH ₂ −Z—CH ₂ , where Z is. Either O, NH, S, OCO or CO, where R ¹¹ is

R ¹¹ is attached to ^{R 10} at any of the 3, 4, 5, 6, 7 or 8 positions of ^{R 11 , and R 12 to} R ¹⁷ are H, C _{1 to 18} alkyl, C _{1 to 1. 18} or in either of the aryl or removed, provided ^{that if R 11} is bonded to ^{R 10} in the 3-position of ^{R 11, R 12} is ^{removed, R 10} at the 4-position of ^{R 11} is ^{R 11} If R ¹³ is removed and R ¹¹ is ^{attached to R 10} at the 5th position of R ¹¹ , then R ¹⁴ is removed and R ¹¹ is attached ^{to R 10} at the 6th position of R ^11. If R ¹⁵ is removed and R ¹¹ is ^{bound to R 10} at the 7th position of ^{R 11} , then R ¹⁶ is removed and R ¹¹ is bound to ^{R 10} at the 8th position of R ^11. are ^{case, R 17} is removed)
Is one of
However, ^{one of R 1 to} R ⁶ is other than H, and the C atoms at positions 2 and 9 of 1,10-phenanthroline are each bonded to H by a bond that does not participate in the fused ring structure. ,
One of R ^{1 to} R ⁶ contains a spacer and an acidic group, preferably R ¹ or R ⁶ contains a spacer and an acidic group]
Phenanthroline compound.

In a further embodiment of the present specification, R ^{1 to} R ⁶ have a total of at least 6 carbon atoms, such as 6, 7, 8, 9, 10 or 11 carbon atoms, for example, a total of at least 11 carbon atoms. Contains carbon atoms of, for example, 11-18 carbon atoms.

In another embodiment, ^{one or more of R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is an alkyl or aryl group having 1 to 18 carbon atoms. For example, ^{one or two groups selected from R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ can be alkyl or aryl groups with 1-18 carbon atoms, the others. Hydrogen, for example, R ¹ and R ² , R ¹ and R ³ , R ¹ and R ⁴ , R ¹ and R ⁵ , R ¹ and R ⁶ , R ² and R ³ , R ² and R ⁴ , R ² And R ⁵ , R ² and R ⁶ , R ³ and R ⁴ , R ³ and R ⁵ , R ³ and R ⁶ , R ⁴ and R ⁵ , R ⁴ and R ⁶ or R ⁵ and R ⁶ are 1 to 18 It is an alkyl or aryl group with a number of carbon atoms, the other being hydrogen.

In another embodiment, ^{one or more of R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is an alkyl group having 1 to 18 carbon atoms. For example, ^{one or two groups selected from R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ can be alkyl groups with 1-18 carbon atoms, the other with hydrogen. Yes, for example, R ¹ and R ² , R ¹ and R ³ , R ¹ and R ⁴ , R ¹ and R ⁵ , R ¹ and R ⁶ , R ² and R ³ , R ² and R ⁴ , R ² and R. ⁵ , R ² and R ⁶ , R ³ and R ⁴ , R ³ and R ⁵ , R ³ and R ⁶ , R ⁴ and R ⁵ , R ⁴ and R ⁶ or R ⁵ and R ⁶ are 1 to 18 pieces. It is an alkyl group having a carbon atom, and the others are hydrogen.

In another embodiment, ^{one or more of R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is an alkyl group having 6-18 carbon atoms. For example, ^{one or two groups selected from R 1} , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ can be alkyl groups with 6-18 carbon atoms, the other with hydrogen. Yes, for example, R ¹ and R ² , R ¹ and R ³ , R ¹ and R ⁴ , R ¹ and R ⁵ , R ¹ and R ⁶ , R ² and R ³ , R ² and R ⁴ , R ² and R. ⁵ , R ² and R ⁶ , R ³ and R ⁴ , R ³ and R ⁵ , R ³ and R ⁶ , R ⁴ and R ⁵ , R ⁴ and R ⁶ or R ⁵ and R ⁶ are 6 to 18 pieces. It is an alkyl group having a carbon atom, and the others are hydrogen.

In another ^embodiment, one of ^{R 1, R 2, R 3} , R 4, R 5 and ^{R 6,} 1 to 18 carbon atoms, for example, 6 to 18 carbon atoms, for example, 11 It is an alkyl group having ~ 18 carbon atoms.

In another embodiment, R ² and / or R ⁵ is an alkyl group having 1 to 18 carbon atoms, eg, 6 to 18 carbon atoms, eg, 11 to 18 carbon atoms.
In another embodiment, R ² and / or R ⁵ is an aryl group having 1 to 18 carbon atoms.

In a preferred embodiment, the phenanthroline compound is 4-undecylic-1, 10-phenanthroline covalently attached to an acidic group via a spacer, said spacer having at least one carbon atom, eg, 2 or 3 carbon atoms. Contains carbon atoms of.

In another preferred embodiment, the phenanthroline compound is 4,7-diundesyl-1,10-phenanthroline covalently attached to an acidic group via a spacer, said spacer containing at least one carbon atom.

Preferably, the spacer contains 1-18 carbon atoms. In one embodiment, the spacer comprises at least two, for example, at least three carbon atoms, and the spacer is located at the 2, 3, 4, 5, 6, 7, 8 or 9 position of the 1,10-phenanthroline compound. Covalently bonded.

In one embodiment, the acidic group is selected from the group consisting of carboxylic acid, sulfonic acid, sulfuric acid monoester, sulfonamide, phosphonic acid, phosphoric acid, arsenic, sulfinic acid or thiocarboxylic acid.

In a preferred embodiment, the acidic group is − (HPO ₄ ) R ⁷ , − (HPO ₃ ) R ⁷ (where R ⁷ is H, alkyl, branched alkyl, aryl or substituted aryl), eg 4- Octylphenyl.

In another embodiment, the ionophore has a tripod stereochemical structure, eg, one of the structures represented by formulas IV, V, VI and VII. In one further embodiment of the specification, the acidic group is located distal to the malondiamide group on one, two or three arms of the structure represented by formula IV, V, VI or VII. In this context, "distal" means distal to the center of the tripod-shaped structure. Preferably, only one arm of the molecule has a covalently bonded acidic group. In another embodiment, in one of the three arms of the structure represented by the formula IV, V, VI or VII, the marrondiamide group is partially or completely replaced with an acidic group.

Additional Membrane Components Plasticizers-The membranes of the present invention typically contain additional plasticizers. The role of the plasticizer is to keep other components, such as ionophore, solvated. Many suitable plasticizers, such as esters, phosphonates and ethers, have been described in the art. In one embodiment, the plasticizer is 4-hexylphenyl 2-nitrophenyl ether (NHPE) or 2-nitrophenyl octyl ether (NPOE) or a mixture thereof. In one embodiment, the plasticizer, eg NHPE, constitutes from about 40% to 80% of the mass of the dry membrane, eg 50% to 70% of the mass of the dry membrane, eg 55% to 65% of the mass of the dry membrane. ..

Polymers-The membranes of the present invention typically further include polymers or mixtures of polymers, polymer blends. The polymer imparts structural integrity to the membrane by providing a network for containing the plasticizer and the active ingredient. Non-limiting examples of polymers and copolymers that can be used include poly (vinyl chloride), carboxylated (polyvinyl chloride), polyurethane, poly (vinyl chloride-co-vinyl acetate), poly (vinyl chloride-co-vinyl alcohol). , Poly (vinyl chloride-co-vinyl acetate-co-vinyl alcohol) and combinations thereof.

In a preferred embodiment, the membrane comprises a polymer blend, said polymer blend.
1. 1. The first polymer, which is a carboxylated polyvinyl (vinyl chloride) or poly (vinyl chloride), wherein the first polymer has a molecular weight of 100,000 to 500,000.
2. A second polymer, which is a copolymer of vinyl chloride and at least one additional monomer group having a hydrophilic group, wherein the second polymer has a molecular weight of less than 100,000. Including
When the first polymer is carboxylated polyvinyl chloride, the second polymer has more hydrophilic groups than the first polymer.

In one embodiment, the first polymer is carboxylated polyvinyl chloride. In a further embodiment, the first polymer is carboxylated polyvinyl chloride, and the second polymer has at least 1.5 times more hydrophilic groups than the first polymer, eg, the first polymer. Has at least 2-fold, eg, at least 4-fold, eg, at least 5-fold, eg, at least 10-fold, hydrophilic groups of the polymer. In yet further embodiments, the first polymer is carboxylated polyvinyl chloride, and the carboxylated polyvinyl chloride is 0.1% to 10% carboxylated, eg, 0.5% to. It is 5% carboxylated, eg, 1% to 3% carboxylated, eg, 1.8% carboxylated.

In another embodiment, the first polymer is poly (vinyl chloride).
In one embodiment, the molecular weight of the first polymer is at least 110,000, eg, at least 120,000, eg, 130,000-400,000, eg, 130,000-300,000, eg 130, It is 000 to 250,000.

In one embodiment, the first polymer is carboxylated polyvinyl chloride, and the molecular weight of the first polymer is at least 110,000, eg, at least 120,000, eg, 130,000-400. 000, for example 200,000 to 300,000, for example 200,000 to 250,000, for example 220,000.

In another embodiment, the first polymer is poly (vinyl chloride) and the molecular weight of the first polymer is at least 110,000, eg, at least 120,000, eg, 120,000-200, 000, for example 130,000 to 160,000, for example 140,000.

In one embodiment of the membrane of the present invention, the additional monomer in the second polymer is vinyl alcohol, vinyl ester or hydroxyfunctional acrylate. In a further embodiment, the second polymer is a copolymer of vinyl chloride, vinyl acetate, vinyl alcohol and an additional monomer, optionally containing a hydrophilic group such as acrylic acid, methacrylic acid or maleic acid.

In yet further embodiments, the second polymer is poly (vinyl chloride-co-vinyl acetate-co-vinyl alcohol). In one embodiment, the poly (vinyl chloride-co-vinyl acetate-co-vinyl alcohol) is 75% to 98% vinyl chloride, eg 85% to 95% vinyl chloride, eg 89% to 93%. Contains vinyl chloride, eg, 91% vinyl chloride. In another embodiment, the poly (vinyl chloride-co-vinyl acetate-co-vinyl alcohol) is 1% to 20% vinyl acetate, eg, 1% to 10% vinyl acetate, eg, 1% to 5 Includes% vinyl acetate, eg 3% vinyl acetate. In a further embodiment, the poly (vinyl chloride-co-vinyl acetate-co-vinyl alcohol) is 1% to 15% vinyl alcohol, eg, 1% to 10% vinyl alcohol, eg, 4% to 8%. Vinyl alcohol, eg, 6% vinyl alcohol.

In one embodiment, the molecular weight of the second polymer is less than 100,000, such as 30,000 to 90,000, preferably 60,000 to 80,000, such as 70,000.

In one embodiment, the ratio of the mass of the first polymer to the mass of the second polymer in the membrane is 10: 1 to 1: 5, such as 4: 1 to 1: 4, for example 2: 1 to 1: 1. 3, for example, 2: 3 to 3: 7, for example 1: 2.

In one embodiment, the first polymer is carboxylated polyvinyl chloride, and the ratio of the mass of the first polymer to the mass of the second polymer in the film is 4: 1 to 1: 4, for example. 2: 1 to 1: 3, for example 3: 2 to 3: 7, or 2: 3 to 3: 7, for example 1: 2.

In another embodiment, the first polymer is poly (vinyl chloride) and the ratio of the mass of the first polymer to the mass of the second polymer in the membrane is 10: 1 to 1: 5, for example. 7: 1 to 1: 2, for example 5: 1 to 1: 2, for example 5: 1 to 2: 3, for example 5: 1 to 2: 1, for example 4: 1.

In one embodiment, the polymer blend is about 10% to 50% of the dry membrane mass (ie, the mass of the components before being mixed in the solvent), eg 20% to 40% of the dry membrane mass, eg dry. It constitutes 25% to 35% of the membrane mass, for example 25% to 30% of the dry membrane mass. In a preferred embodiment, the membrane has the composition specified in Table 1 below.

Methods for Preparing Membranes of the Invention In a further embodiment, the invention comprises mixing components in a solvent, distributing the resulting solution onto a desired support, and evaporating the solvent to cause the magnesium ions of the invention. It relates to a method of preparing a selective membrane. Any suitable solvent can be used. In one embodiment, the solvent is cyclohexanone. The support can be flexible or rigid. The support is preferably a non-conductive material such as silicon, polymer, printed circuit board (PCB), flex PCB, polyethylene terephthalate (PET), polyimide (PI), ceramic, alumina, glass, wood products, frit and the like. is made of.

Electrodes and Potential Difference Measuring Sensors In a further primary aspect, the invention relates to ion-selective electrodes, including the magnesium ion-selective membranes of the invention described herein. The electrodes can be made by using thick film methods such as screen printing, rotary gravure printing, pad printing, stencil printing conductive materials such as carbon, Cu, Pt, Pd, Au and / or nanotubes, or. It can be made on a support by using a thin film method, eg, a conductive material of sputtering, thermal spray and / or cold spray. The support can be flexible or rigid. The support is preferably a non-conductive material such as silicon, polymer, printed circuit board (PCB), flex PCB, polyethylene terephthalate (PET), polyimide (PI), ceramic, alumina, glass, wood products, frit and the like. Made of.

In yet a further primary aspect, the invention relates to a sensor assembly in which two or more sample electrodes are present on a single support with or without a reference electrode (US patent for sensor assembly containing reference electrode). See No. 5916425). In some embodiments, the sensor assembly is made up of two supports, each containing two or more sample electrodes, with or without a reference electrode. The supports may be arranged in a layered structure on top of each other so that the surfaces of the supports having electrodes face each other (eg, WO2008 / 131767). Other suitable sensor assemblies are described in WO2018 / 112017, WO2018 / 112012, WO2018 / 112008, WO2017 / 120464, WO2017 / 019609, WO2016 / 106320, WO2016 / 011308, WO2016 / 007716 and WO2013 / 163120.

In one embodiment, the system is calibrated with a calibrator containing physiological concentrations of potentially interfering compounds (Ca ²⁺ , K ⁺ and Na ^+).
In some embodiments, the system contains one or more electrodes for the measurement of other cations such as calcium ions, so interference is minimized by chemometric correction of the sample signal based on the measurement of cation activity. It can be suppressed to the limit.

Use and Method of Use As described above, in a further primary aspect, the present invention relates to the use of the potential difference measuring sensor or electrode of the present invention to determine the magnesium ion concentration in a sample.

Similarly, the present invention is a method for determining the magnesium ion concentration of a liquid sample, which is obtained from the step of contacting the sample with the electrode of the present invention or the potential difference measuring sensor of the present invention and the electrode or the potential difference measuring sensor. The present invention relates to a method comprising determining the magnesium ion concentration based on the signal obtained.

Biological samples tested for the presence of specimens are physiological fluids such as diluted or undiluted whole blood, serum, plasma, saliva, urine, feces, pleural fluid, cerebrospinal fluid, synovial fluid, milk, ascites, ascitic fluid. It can be liquid or amniotic fluid. Examples of other biological samples include fermented broth, cultured microorganisms, wastewater, foods and the like.

In a preferred embodiment, the sample is a blood sample or a serum sample. The sample, eg, a blood sample, a serum sample, a plasma sample or a pleural sample can be, for example, a sample from a human subject.

The purpose of determining magnesium ion levels is, for example, to diagnose a disease or disorder in a patient, such as a human patient, or to receive treatment such as medical therapy or surgery, or to monitor the magnesium level of a patient enrolled in them. It can be. In one embodiment, the disease or disorder is a cardiovascular disease or disorder. In another embodiment, the sample is from a newborn, i.e., an infant <28 days old.

Zhang (2011) Am J Biomed Sci 3: 301 summarizes several studies demonstrating an association between magnesium levels, especially hypomagnesium and clinical outcomes. For example, the study demonstrated an association between hypomagnesium and the mortality of ICU patients undergoing hemodialysis, type 2 diabetes, cardiovascular disease or medical surgical intensive care. In addition, magnesium deficiency has been found to contribute to coronary spasms, arrhythmias, fibrillation, infarction and sudden death in patients with heart disease. Magnesium intervention studies during cardiopulmonary bypass showed that intraoperative correction of iMg was associated with reduced postoperative ventricular arrhythmias and maintenance of continuous sinus rhythm. Clinical trial results also suggest the benefits of magnesium therapy for patients with acute stroke in an ambulance or emergency department within 2 hours of the onset of stroke symptoms. Magnesium monitoring is a condition that has been reported to be associated with hypomagnesium and is also advocated for preeclampsia, which occurs in 5-7% of pregnancies in Europe and USA. Other findings suggest that the iCa: iMg ratio is a crucial diagnostic parameter for the prevention of vascular and nervous system complications in patients with preeclampsia-eclampsia. Soliman et al. (2003) Crit. Care Med. 31: 1082 reported a correlation between the onset of ionized hypomagnesium during the ICU stay and high morbidity and mortality.

Thus, in a further embodiment, the sample whose magnesium ion level is determined by the method or use of the invention is, for example, an acutely hospitalized patient, or undergoes medical therapy or surgery, such as cardiac surgery, such as cardiopulmonary bypass surgery. Alternatively, it may be a sample from a patient enrolled in these. In a further embodiment, the sample is taken from a patient with poor food intake, malabsorption, hypokalemia, hypocalcemia, alcoholism, or a diuretic or other drug associated with hypomagnesium. It is from a patient who does. In a further embodiment, the sample is a renal disease, hypertension, prenatal disease, diabetes mellitus, diabetic ketoacidosis, arrhythmia, sepsis, chest pain, acute stroke, traumatic shock (chock), burn / smoke inhalation, acute lung disease or heart. It is from a patient with a disease, eg, cardiac arrest. In another embodiment, the patient is a patient in an obstetrics ward or a patient undergoing hemodialysis. In addition, the sample can be from an ICU patient undergoing hemodialysis, type 2 diabetes, cardiovascular disease or medical surgical intensive care.

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

Example 1
Preparation of ion-selective membrane Prepare a storage solution of hemimagnesium bis [4-octylphenyl] phosphate (MgOPP) by mixing MgOPP and cyclohexanone (> 99.8%) at a ratio of 48.28 g of cyclohexanone per 1 g of MgOPP. bottom. The compounds were mixed at room temperature and then stirred at room temperature in the dark for a minimum of 8 hours or at 37 ° C. for a minimum of 4 hours.

A solution for distributing the membrane was prepared by mixing the following components.

The compounds were mixed in a vial filled with argon or nitrogen gas at room temperature and then stirred at room temperature in the dark for a minimum of 40 hours or at 37 ° C. for a minimum of 16 hours. Using the resulting solution, the membrane was dispensed onto a gold electrode covered with poly (3,4-ethylenedioxythiophene) -poly (styrene sulfonate) (PEDOT) on a ceramic support. Then, the solvent was evaporated to obtain a plasticized ion-selective membrane.

Example 2
Membrane Performance Containing Lipophilic Salts Two membranes containing phenanthroline-based ionophores and lipophilic tetraxborate were prepared and tested for the effect of lipophilic salt addition on membrane performance. The lipophilic salts tested were hemicalcium bis [4-octylphenyl] phosphate and hemicalcium bis [4- (1,1,3,3-tetramethylbutyl) -phenyl] phosphate.

Two membranes were prepared as described in Example 1, except that the composition was as follows:

Each membrane was dispensed on three individual electrodes of the electrode array. It ^{also contained a Ca 2+} ion-selective electrode. Membranes were dispensed as described in Example 1, except that vanadium bronze was used as the transducer material instead of PEDOT. The resulting ion-selective electrode array was placed in the measurement chamber within the test analyzer. The measurement chamber was in fluid contact with the reference electrode. The test analyzer was programmed to transport the calibration and rinse fluids, aspirate the sample, sample the potential difference signal at each electrode position, and automatically control the acquisition of these data.

The Mg ²⁺ ion-selective electrode was calibrated with three different calibration solutions containing ^{Mg 2+} and Ca ^{2+ ions in three different ratios.} The state value (E0), sensitivity (S), and selection coefficient (K) of Mg ^{2+ ions with respect to Ca 2+} ions were determined based on the electrode signal obtained with the calibration solution. The Ca ²⁺ ion-selective electrode was also calibrated. The calibrated sensor was then subjected to the measurements below:
-Five types of aqueous samples with a concentration range of 0.1 mM to 2.5 mM Mg ^{2+ ions.}
-Whole blood from a healthy donor. The same sample was repeatedly measured 5 times. ^{In addition, the concentration of Mg 2+} ions in the sample was determined by measurement with a NOVA8 analyzer from NOVABiomedical.
Low and high concentrations of potentially interfering Zn ²⁺ ions: Prepared with 5% bovine serum albumin (BSA) and a constant concentration of 0.5 mM Mg ^{2+ ions corresponding to normal physiological concentrations in plasma.} 0 μM, 20 μM and 200 μM in the prepared solution
For each Mg ²⁺ ion-selective electrode, ^{the concentration of Mg 2+} ions (cMg) in the sample is determined by the calibration parameter (E0, S and K) values and Ca ²⁺ ion-selective electrode determined for the electrode prior to sample measurement. It was calculated from the signal obtained in a specific sample using the concentration of ^{Ca 2+ ions.} For the calculation of the ion Mg ²⁺ concentration, the Nicolsky-Eisenmann (NE) equation was used as a sensor response model according to IFCC guidelines (Ben Rayana et al. (2008) Clin Chem Lab Med46 (1): 21). No subsequent corrections were made to obtain the listed cMg values.

CONCLUSIONS The membrane worked similarly well for the measurement of aqueous samples with ^{known concentrations of Mg 2+ ions.} However, when comparing the cMg results read by the NOVA8 analyzer, the deviation of the blood sample of film 1 was smaller than that of film 2 (Table 3 (0.685 / 0.685 / 0.68 is 0.947 / 0). The deviation from 0.614 is smaller than that of .931 / 0.963)). In addition, it was observed that the interference of zinc ions was small in Membrane 1 (Table 4 (value of Membrane 1 (0.514 / 0.542 / 0.815) shows Membrane 2 (0.777 / 0.888/2). It is closer to 0.5 mM than the value of .896)).

Example 3
Membrane Performance Containing Single Lipophilic Acid or Acidate Five membranes containing a phenanthroline-based ionophore and a single lipophilic salt were prepared to prepare a single lipophilic acid (or acid salt) for membrane performance. ) Was tested. 4 kinds of lipophilic acids (acid salts): Mx = {calcium; magnesium} Hemi Mxbis [4-octylphenyl] phosphate [Mx (OPP) ₂ ], 4-octylbenzoic acid (OBA), 4-octyl Sodium benzenesulfonate (OBS) and sodium 4-dodecylbenzenesulfonate (DBS) were tested. A lipophilic salt used as a standard in ion-selective electrodes: potassium tetrakis (4-chlorophenyl) borate was also tested.

Five membranes were prepared as described in Example 1, except that the _{composition was as follows and only Mg (OPP) 2} was pre-dissolved in cyclohexanone prior to the addition of the remaining components. The composition was such that the lipophilic anions in the membrane were surely at the same concentration.

Each film was dispensed on four identical electrodes, each placed on the same electrode array. It also contained a Ca ²⁺ ion-selective electrode. Membranes were dispensed as described in Example 1. Each electrode array was placed in the measurement chamber within the test analyzer as described in Example 2.

The Mg ²⁺ ion-selective electrode was calibrated as described in Example 2, but co-calibration of other sensors such as Na, K, Ca, Cl, pH, pO ₂ , pCO ₂ , glucose and lactate sensors. Calibrated with a more complex solution matrix suitable for. The Ca ²⁺ ion-selective electrode was also calibrated. The calibrated sensor was then subjected to the measurements below:
SSM (single solution method) solution: Two types of aqueous samples in which ^{one sample contains 100 mM Mg 2+} ions and the other sample ^{contains 100 mM Ca 2+ ions.} All samples had a constant background of 5 mM HEPES buffer titrated to pH = 7.4 at 37 ° C. and 160 mM ionic strength (adjusted by the addition of NaCl).
FIM (fixed interference method) solution: 1.25 mM Ca ²⁺ ions, 5 mM HEPES buffer titrated to pH = 7.4 at 37 ° C. and a constant background of 160 mM ionic strength (adjusted by the addition of NaCl). Eight kinds of aqueous samples having a concentration of Mg ²⁺ ions {0.01; 0.05; 0.10; 0.50; 1.00; 5.00; 10.00; 50.00}.
Standard solution: 1.25 mM Ca ²⁺ ions, 5 mM HEPES buffer titrated to pH = 7.4 at 37 ° C. and a constant background of 160 mM ionic strength (adjusted by addition of NaCl) from 0.2 mM to 2. Five aqueous samples over a physiologically appropriate concentration range of 5 mM Mg ^{2+ ions.}

For each Mg ²⁺ ion-selective electrode, ^{the concentration of Mg 2+} ions (cMg) in the sample was calculated as described in Example 2. Selection factor determined from measurements in SSM and / or FIM solution

And sensitivity was calculated directly based on the electrode signals according to the Single Liquid Method (SSM) and Fixed Interferometry (FIM) described in Umezawa et al. (2000) Pure Appl Chem 72: 1851.

Results and Conclusions The OPP and DBS membranes have a linear response gradient over the upper cMg range spread in the FIM solution (Fig. 1). The response gradient is close to the theoretically expected Nernst sensitivity (about 30 mV / decade) to divalent ions (Table 5). The other three membranes do not have a linear response gradient within the above range and therefore cannot calculate a meaningful selection factor based on the FIM solution. Therefore, the change in response signal to changes in cMg is very low, if not zero, in that range, so these membranes have a physiologically appropriate cMg range (0.2) at physiological cCa and cNa background levels. Not immediately applicable to measurements within ~ 2.5 mM) (Fig. 1). ^{However, OBA and OBS membranes show improved Mg selectivity compared to both Ca 2+} and Na ⁺ ions compared to tetrakis variants (see below) and are therefore used in higher Mg ranges. It was possible, or some optimization of the amount of ingredients could make it more suitable for the physiological range. Notably, the Tetrakis membrane has a negative signal response to a FIM solution of cMg = 50 mM. The concentration of sodium ions is very low in this solution (about 20 mM) compared to other FIM solutions (about 124-155 mM), which means that the tetrakis membrane affects high levels of interference from sodium ions. Indicates to receive.

None of the membranes containing lipophilic acids (or acid salts) behave similarly to tetrakis membranes with respect to changes in sodium ion concentration (FIG. 1). Also, comparing the selectivity based on the SSM solution, all of these films have a selectivity of 1 or less (Table 5). That is, these membranes selectively respond to ^{Mg 2+} ions rather than ^{Ca 2+ ions.} In contrast, Tetrakis membranes have a selectivity factor greater than 1 (Table 5), which means they are less selective for ^{Mg 2+ ions than Ca 2+ ions.} Therefore, all four membranes containing lipophilic acids (or acid salts) are Mg selective compared to both ^{Ca 2+} and Na ^{+ ions compared to tetrakis variants containing standard lipophilic salts.} Was improved.

Calibrating the membrane against a complex solution background, suitable for simultaneous calibration of other sensors such as Na, K, Ca, Cl, pH, pO ₂ , pCO _{2, glucose and lactate sensors, provides calibrated sensitivity and} The best match between the selectivity and those based on FIM and SSM solutions is obtained with the OPP membrane (Table 5). Therefore, this membrane is most accurately and accurately measured with standard solutions corresponding to the physiologically appropriate cMg range (Table 6). Since the tetrakis membrane could not be calibrated in a complex solution background, the calibration or cMg values in standard solution are not shown for the tetrakis membrane (Tables 5 and 6), ie Nicolsky-Eisenmann (NE). No physically meaningful solution was found for the equation, which again means that the Tetrakis membrane is also a significant choice for ^{other ions than Mg 2+} and Ca ²⁺ ions, such as Na ^{+ ions.} Indicates that it has sex.

Example 4
Membrane Performance Containing Alternative Ionophores When five membranes containing Mg selective ionophores and a single lipophilic salt were prepared and used in combination with a single lipophilic acid (or acid salt). The effect on membrane performance was tested. Three types of ionophores: 4,7-diundesyl-1,10-phenanthroline [DUP], 4-undecyl-1,10-phenanthroline [MUP] and ETH5506 as lipophilic salts Mx (OPP) ₂ (Mx = {calcium) Tested in combination with HemiMxbis [4-octylphenyl] phosphate), which is magnesium}. DUP and ETH5506 were also tested in combination with tetrakis (tetrakis- (4-chlorophenyl) potassium borate) as a lipophilic salt.

Five membranes were prepared as described in Example 1, except that the _{composition was as follows and only Mg (OPP) 2} was pre-dissolved in cyclohexanone prior to the addition of the remaining components. The composition was such that the concentration of ionophore in the membrane and the concentration of lipophilic anion were surely the same ratio. The amount of the two membranes containing the ETH5506 ionophore was reduced to less than one-sixth that of the one containing the DUP ionophore and the one containing the MUP ionophore. The membrane containing the DUP ionophore is identical to the "OPP" and "Tetrakis" membranes described in Example 3.

Each film was dispensed on four identical electrodes, each placed on the same electrode array. It also contained a Ca ²⁺ ion-selective electrode. Membranes were dispensed as described in Example 1. Each electrode array was placed in the measurement chamber within the test analyzer as described in Example 2.

The Mg ²⁺ ion-selective electrode was calibrated as described in Example 3. The Ca ²⁺ ion-selective electrode was also calibrated. The calibrated sensor was then subjected to measurements in SSM solution, FIM solution and standard solution as described in Example 3.

For each Mg ²⁺ ion-selective electrode, ^{the concentration of Mg 2+} ions (cMg) in the sample was calculated as described in Example 2. Selection factor determined from measurements in SSM and / or FIM solution

And sensitivity were calculated as described in Example 3.

Results and Conclusions The DUP_OPP and MUP_OPP films have a linear response gradient over the upper cMg range spread in the FIM solution (Fig. 2). The response gradient is close to the theoretically expected Nernst sensitivity (about 30 mV / decade) to divalent ions (Table 7). The other three membranes do not have a linear response gradient within the above range and therefore cannot calculate a meaningful selection factor based on the FIM solution. Therefore, the change in response signal to changes in cMg is very low, if not zero, in that range, so these membranes have a physiologically appropriate cMg range (0.2) at physiological cCa and cNa background levels. Not immediately applicable to measurements within ~ 2.5 mM) (Fig. 2). However, the ETH5506_OPP membrane showed less interference from sodium ions compared to the Tetrakis mutant (see below) and could therefore be used in higher Mg ranges or some of the component amounts. The optimization allowed us to make it more suitable for the physiological range. It should be noted that all the membranes containing the tetrakis salt (DUP_tetrakis and ETH5506_tetrakis) have a negative signal response to the FIM solution of cMg = 50 mM. The concentration of sodium ions is very low in this solution (about 20 mM) compared to other FIM solutions (about 124-155 mM), which means that the tetrakis-containing membrane has high levels of interference from sodium ions. Shows that it is affected by.

None of the membranes containing lipophilic salts (Mx (OPP) ₂ ) behave similarly to tetrakis membranes with respect to changes in sodium ion concentration (FIG. 2). Comparing the selectivity based on the SSM solution, all of these membranes have a selectivity of 1 or less, except for ETH5506_OPP (Table 7). That is, the membrane selectively responds to ^{Mg 2+} ions rather than ^{Ca 2+ ions.} In contrast, both the tetrakis salt-containing membranes (DUP_Tetrakis and ETH5506_Tetrakis) and ETH5506_OPP have a selectivity of more than 1 (Table 7), which are less selective for ^{Mg 2+ ions than Ca 2+} ions. Means. Therefore, all membranes containing lipophilic acid salt (Mx (OPP) ₂ ) show improved Mg-selectivity compared to ^{Na + ions compared to membranes containing standard lipophilic tetrakis salts.} rice field. In addition, the combination of lipophilic salts and phenanthroline-based ionophores (DUP_OPP and MUP_OPP) improves Mg-selectivity compared to ^{Ca 2+ ions compared to ETH5506_OPP membranes containing non-phenanthroline-based ionophores.}

Calibrating the membrane against a complex solution background, suitable for simultaneous calibration of other sensors such as Na, K, Ca, Cl, pH, pO ₂ , pCO _{2, glucose and lactate sensors, provides calibrated sensitivity and} The best agreement between the selectivity and those based on FIM and SSM solutions is obtained with the DUP_OPP and MUP_OPP membranes (Table 7). Therefore, these membranes are most accurately and accurately measured with standard solutions corresponding to the physiologically appropriate cMg range (Table 8). Since the membrane containing the tetrakis salt could not be calibrated in a complex solution background, the calibration value or cMg value in the standard solution is not shown for the membrane containing the tetrakis salt (Tables 7 and 8), ie. No physically meaningful solution to the Nicholsky-Eisenmann (NE) equation could be found, again because the tetrakis salt-containing membrane is also an ion other than the ^{Mg 2+} and Ca ^{2+ ions.} For example, it is shown to have significant selectivity for ^{Na + ions.}

Claims (21)

a. Ionophore, and b. A lipophilic compound containing an acidic group, of formula I

(During the ceremony,
A contains an acidic group
One, two or all three of R ¹⁸ , R ¹⁹ and R ²⁰ _{are C 4-18} alkyl groups, C _4-18 alkenyl groups, C _4-18 alkynyl groups or amide-containing C _4-18 groups. a _{C 4 to 18} group is the _{C 4 to 18} groups, or 1, 2 and 3, calculated from the phenyl group is a straight chain or a side chain in total the 1, 2 and 3 of Have only one
The other R ¹⁸ , R ¹⁹ and R ²⁰ are independently hydrogen or linear C _1-18 alkyl groups).
A magnesium ion-selective membrane containing a lipophilic compound, or a salt of the lipophilic compound, which is a compound of the above. The membrane according to claim 1, wherein the ionophore is not charged. The membrane according to claim 1 or 2, wherein the ionophore is 1,10-phenanthroline or a phenanthroline compound which is a substitute form thereof. The phenanthroline compound is of formula II

[During the ceremony,
R ^{1 to} R ⁶ are each
H,
Either F, Cl, Br, I, NO ₂ , CN or CF _3,
C _1-18 alkyl,
C _1-18 aryl,
C _1-18 alkenyl,
(CH ₂ ) _m Y (in the equation, m is an integer of 0 or 1-4, where Y is -OR ⁷ , -NR ⁷ R ⁸ , -OCOR ⁷ , -NR ⁷ COR ⁸ , -COR ⁷ , -COOR. ⁷ , -SO ₃ R ⁷ , -OSiR ⁷ R ⁸ R ⁹ , -PO ₄ R ⁷ R ⁸ , -PO ₃ R ⁷ R ⁸ , where R ⁷ , R ⁸ and R ⁹ are H, respectively. Alkyl, branched alkyl, aryl or substituted aryl), or C _n −R ¹⁰ R ¹¹ (in the formula, n is an integer of 1 to 17 including 0, or 1 and 17, where R ¹⁰ is C. , N, NCO or CH _2- Z-CH ₂ , where Z is either O, NH, S, OCO or CO and R ¹¹ is

R ¹¹ is attached to ^{R 10} at any of the 3, 4, 5, 6, 7 or 8 positions of ^{R 11 , and R 12 to} R ¹⁷ are H, C _{1 to 18} alkyl, C _{1 to 1. 18} or in either of the aryl or removed, provided ^{that if R 11} is bonded to ^{R 10} in the 3-position of ^{R 11, R 12} is ^{removed, R 10} at the 4-position of ^{R 11} is ^{R 11} If R ¹³ is removed and R ¹¹ is ^{attached to R 10} at the 5th position of R ¹¹ , then R ¹⁴ is removed and R ¹¹ is attached ^{to R 10} at the 6th position of R ^11. If R ¹⁵ is removed and R ¹¹ is ^{bound to R 10} at the 7th position of ^{R 11} , then R ¹⁶ is removed and R ¹¹ is bound to ^{R 10} at the 8th position of R ^11. are ^{case, R 17} is removed)
Is one of
However, ^{one of R 1 to} R ⁶ is other than H, and the C atoms at positions 2 and 9 of 1,10-phenanthroline are each bonded to H by a bond that does not participate in the fused ring structure. ]
The film according to claim 3, which is a compound of the above. The film according to claim 4, wherein R ^{1 to} R ⁶ contain a total of at least 6 carbon atoms, for example, a total of at least 11 carbon atoms. One or more of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are alkyl groups having 1 to 18 carbon atoms, for example R ² and / or R ⁵ The film according to claim 4 or 5, which is an alkyl group having 1 to 18 carbon atoms. The membrane according to any one of claims 4 to 6, wherein the phenanthroline compound is 4-undecylic-1,10-phenanthroline or 4,7-diundesyl-1,10-phenanthroline. 1. The acidic group contained in the A group of the formula I is selected from the group consisting of a carboxylic acid, a sulfonic acid, a sulfuric acid monoester, a sulfonamide, a phosphonic acid, a phosphoric acid, a hyric acid, a sulfinic acid or a thiocarboxylic acid. The film according to any one of 1 to 7. The lipophilic compound has the following formula

The membrane according to claim 8, which is a compound of the above. Only one of R ¹⁸ , R ¹⁹ or R ²⁰ _{is a C 4-18} alkyl group as defined in claim 1, the other is hydrogen or a straight chain C _1-18 alkyl group, preferably. The film according to any one of claims 1 to 9, wherein the other is hydrogen. The membrane according to any one of claims 1 to 10, wherein R ¹⁹ _{is a C 4-18} alkyl group as defined in claim 1 and ^{R 18} and R ^{20 are hydrogen.} The film according to any one of claims 1 to 11, wherein the C4 to ₁₈ alkyl groups (s) contain at least 6 carbon atoms, for example, at least 8 carbon atoms. Claims 1 to 12, wherein the lipophilic compound is a lipophilic salt, and the lipophilic salt is hemicalcium bis [4-octylphenyl] phosphate, hemimagnesium bis [4-octylphenyl] phosphate or a mixture thereof. The film according to any one of the above. 13. The mixture according to claim 13, wherein the lipophilic salt is a mixture containing at least 50% hemimagnesium bis [4-octylphenyl] phosphate, for example 80% to 90% hemimagnesium bis [4-octylphenyl] phosphate. Membrane. Claims 1 to 14, wherein the molar ratio of the ionophore to the anion of the lipophilic compound or lipophilic salt is 2: 1 to 1: 1, for example, 1.8: 1 to 1.2: 1. The film according to any one item. i) an ionophore covalently bonded to an acidic group via a spacer, wherein the spacer contains at least one carbon atom, or ii) a salt of the ionophore covalently bonded to an acidic group. Including magnesium ion selective membrane. A method for preparing a magnesium ion-selective membrane, wherein the component according to any one of claims 1 to 16 is mixed in a solvent, and the obtained solution is distributed on a desired support. And a method comprising evaporating the solvent. An electrode for determining the magnesium ion concentration of a liquid sample, which comprises the membrane according to any one of claims 1 to 16. A potentiometric titration sensor for determining the magnesium ion concentration of a liquid sample, the potentiometric titration sensor comprising the electrode and reference electrode according to claim 18. A method for determining the magnesium ion concentration of a liquid sample, which is obtained from the step of contacting the sample with the electrode according to claim 18 or the potentiometric titration sensor according to claim 19 and the electrode or the potentiometric titration sensor. A method comprising the step of determining the magnesium ion concentration based on a signal. A method of diagnosing a disease or disorder comprising performing the method of claim 20 on a sample of interest.

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